The Immunomodulatory Action of Sialostatin L on Dendritic Cells Reveals Its Potential to Interfere with Autoimmunity

Sialostatin L (SialoL) is a secreted cysteine protease inhibitor identified in the salivary glands of the Lyme disease vector Ixodes scapularis. In this study, we reveal the mechanisms of SialoL immunomodulatory actions on the vertebrate host. LPS-induced maturation of dendritic cells from C57BL/6 mice was significantly reduced in the presence of SialoL. Although OVA degradation was not affected by the presence of SialoL in dendritic cell cultures, cathepsin S activity was partially inhibited, leading to an accumulation of a 10-kDa invariant chain intermediate in these cells. As a consequence, in vitro Ag-specific CD4(+) T cell proliferation was inhibited in a time-dependent manner by SialoL, and further studies engaging cathepsin S(-/-) or cathepsin L(-/-) dendritic cells confirmed that the immunomodulatory actions of SialoL are mediated by inhibition of cathepsin S. Moreover, mice treated with SialoL displayed decreased early T cell expansion and recall response upon antigenic stimulation. Finally, SialoL administration during the immunization phase of experimental autoimmune encephalomyelitis in mice significantly prevented disease symptoms, which was associated with impaired IFN-gamma and IL-17 production and specific T cell proliferation. These results illuminate the dual mechanism by which a human disease vector protein modulates vertebrate host immunity and reveals its potential in prevention of an autoimmune disease. The Journal of Immunology, 2009, 182: 7422-7429.

Antioxidant effect of saponin: potential action of a soybean flavonoid on glucose tolerance and risk factors for atherosclerosis

At the present time, much attention is being paid to antioxidant substances because many pathological conditions are associated with oxidative stress. The purpose of the present study was to discover the potency of saponin (2-phenyl-benzopyrane), a soybean flavonoid, with respect to its hypoglycaemic and hypolipidaemic action, and the association of these effects with oxidative stress. Male Wistar rats were divided into two groups (n = 6): control group and saponin-treated group (60 mg/kg) during 30 days. Saponin had no effects on glucose tolerance. Although no changes had been observed in low-density lipoprotein-cholesterol, saponin-treated animals had increased low-density lipoprotein-cholesterol/triacylglycerol ratio and decreased triacylglycerol, very low-density lipoprotein-cholesterol and total/high-density lipoprotein-cholesterol ratio than the control group. Saponin-treated rats showed lower lipid hydroperoxide than control rats, indicating decreased potential to atherosclerosis. No alterations were observed in antioxidant enzymes, superoxide dismutase and glutathione peroxidase, while lipid hydroperoxide were decreased in saponin-treated rats. In conclusion, the beneficial effects of saponin on serum lipids were related to a direct saponin antioxidant activity.

Evaluation of the genotoxic potential due to the action of an effluent contaminated with chromium, by the comet assay in CHO-K1 cultures

The comet assay technique has been considered to be more efficient in the biomonitoring of aquatic environments that the micronucleus and sister chromatid exchange techniques. The comet assay has been used to determine breaks in the DNA strands of organisms exposed to pollutants with a genotoxic potential. The comet technique was applied to CHO-K1 cells in order to evaluate the genotoxic potential of the waters of the Sapucaizinho River (Municipality of Patrocínio Paulista, State of São Paulo, Brazil), which receive tannery effluents and therefore are contaminated with chromium. The results indicated high genotoxicity of the waters collected at sites located downstream from the emission of tannery effluents, where the concentration of chromium was found to be high.

Influence of soil water potential in the action of herbicides on goosegrass (Eleusine indica (L) Gaertn)

Currently, the use of herbicides is essential in a practical and common in agricultural areas, but efficiency of these herbicides can be compromised when applied on plants that thrive in water deficit conditions, due to low uptake and translocation of the product. Therefore, the aim of this study was to compare the efficiency of control ACCase inhibiting herbicides applied post-emergence in plants of Eleusine indica under different soil water contents. The experiment was conducted in a greenhouse and the experimental design was completely randomized design with four replications, consisting of a 9x4 factorial, with the combination of three soil water potentials (-0.03, -0.07 and -1.5 MPa) three herbicides (fluazifop-p -butyl, haloxyfop-methyl and sethoxydim + oil) and four doses (0, 25, 50, and 100 % of the recommended dose). Herbicide application was made in plants in vegetative stage 2-3 tillers. The soil water potential was initiated in the development stage of two leaves, and the water was supplemented until the soil reaches the potential of -0.01 MPa, when it came to minimum pre-determined for each water management. The physiological parameters evaluated were: photosynthetic rate, stomatal conductance, transpiration leaf temperature and plant dry mass. The visual assessments of phytotoxicity were performed at 7 and 14 days after application. The herbicides behaved in different ways according to the used water management. In severe water stress conditions (soil moisture at 8%) only fluazifop-p-butyl herbicide achieved satisfactory control (> 90%) in E. indica plants.

A Potential Plan of Action for Emerald Ash Borer in Nebraska

Abstract Emerald Ash Borer (Agrilus planipennis) (EAB) is an invasive insect pest. It feeds on the cambium tissues of ash tree species. It was first discovered in the United States in 2002 in Detroit, Michigan. Their effects on ash trees are deadly, and it is quickly spreading across the Midwest. Nebraska has not yet been invaded, but confirmed findings continue getting closer and closer. The major problem facing Nebraskans, with regards to EAB, is how to begin preparations to prevent a dramatic economic loss when an infestation does occur. So, to address this problem, I have conducted street and park tree inventories, to determine the amount of ash trees that are contained in Nebraska’s community forests; and with that data I have attempted to create a possible EAB action plan for Nebraska communities. Based on inventory findings, I have calculated that 6% of Nebraska’s community trees are ash, which is a large percentage. Then, I proposed a plan of action for communities that involve planting a diverse landscape, and a combination of ash replacement programs, and treatment for ash that are less valuable or damaged.

Disruption of glucocorticoid action by environmental chemicals: potential mechanisms and relevance

Glucocorticoids play an essential role in the regulation of key physiological processes, including immunomodulation, brain function, energy metabolism, electrolyte balance and blood pressure. Exposure to naturally occurring compounds or industrial chemicals that impair glucocorticoid action may contribute to the increasing incidence of cognitive deficits, immune disorders and metabolic diseases. Potentially, "glucocorticoid disruptors" can interfere with various steps of hormone action, e.g. hormone synthesis, binding to plasma proteins, delivery to target cells, pre-receptor regulation of the ratio of active versus inactive hormones, glucocorticoid receptor (GR) function, or export and degradation of glucocorticoids. Several recent studies indicate that such chemicals exist and that some of them can cause multiple toxic effects by interfering with different steps of hormone action. For example, increasing evidence suggests that organotins disturb glucocorticoid action by altering the function of factors that regulate the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) pre-receptor enzymes, by direct inhibition of 11beta-HSD2-dependent inactivation of glucocorticoids, and by blocking GR activation. These observations emphasize on the complexity of the toxic effects caused by such compounds and on the need of suitable test systems to assess their effects on each relevant step.

The nonsteroidal anti-inflammatory drug indomethacin induces heterogeneity in lipid membranes: potential implication for its diverse biological action.

BACKGROUND: The nonsteroidal anti-inflammatory drug (NSAID), indomethacin (Indo), has a large number of divergent biological effects, the molecular mechanism(s) for which have yet to be fully elucidated. Interestingly, Indo is highly amphiphilic and associates strongly with lipid membranes, which influence localization, structure and function of membrane-associating proteins and actively regulate cell signaling events. Thus, it is possible that Indo regulates diverse cell functions by altering micro-environments within the membrane. Here we explored the effect of Indo on the nature of the segregated domains in a mixed model membrane composed of dipalmitoyl phosphatidyl-choline (di16:0 PC, or DPPC) and dioleoyl phosphatidyl-choline (di18:1 PC or DOPC) and cholesterol that mimics biomembranes. METHODOLOGY/PRINCIPAL FINDINGS: Using a series of fluorescent probes in a fluorescence resonance energy transfer (FRET) study, we found that Indo induced separation between gel domains and fluid domains in the mixed model membrane, possibly by enhancing the formation of gel-phase domains. This effect originated from the ability of Indo to specifically target the ordered domains in the mixed membrane. These findings were further confirmed by measuring the ability of Indo to affect the fluidity-dependent fluorescence quenching and the level of detergent resistance of membranes. CONCLUSION/SIGNIFICANCE: Because the tested lipids are the main lipid constituents in cell membranes, the observed formation of gel phase domains induced by Indo potentially occurs in biomembranes. This marked Indo-induced change in phase behavior potentially alters membrane protein functions, which contribute to the wide variety of biological activities of Indo and other NSAIDs.

Fibroblast growth factor-1 (FGF-1) as a potential therapeutic target for obesity: mechanisms of FGF-1 action in human preadipocytes

No abstract

Investigation of potential intervention targets to improve insulin action: a therapeutic approach

Impaired insulin action (insulin resistance) is a key factor in the pathogenesis of diabetes mellitus. To investigate therapeutic targets against insulin resistance, this thesis explores the mechanism of action of pharmacological agents and exogenous peptides known or suspected to modify insulin action. These included leptin, a hormone primarily involved in the regulation of body weight; sibutramine, an antiobesity agent; plant-derived compounds (pinitol and chamaemeloside) and agents known to affect insulin sensitivity, e.g. metformin, tolbutamide, thiazolidinediones, vanadyl sulphate and thioctic acid. Models used for investigation included the L6 skeletal muscle cell line and isolated skeletal muscles. In vivo studies were undertaken to investigate glycaemia, insulinaemia, satiety and body weight in streptozotocin-induced diabetic mice and obese (ob/ob) mice. Leptin acutely altered insulin action in skeletal muscle cells via the short form of the leptin receptor. This direct action of leptin was mediated via a pathway involving PI 3-kinase but not Jak2. The active metabolites of sibutramine had antidiabetic properties in vivo and directly improved insulin sensitivity in vitro. This effect appeared to be conducted via a non-PI 3-kinase-mediated increase in protein synthesis with facilitated glucose transport, and was independent of the serotonin and noradrenaline reuptake inhibition produced by sibutramine. Pinitol (a methyl inositol) had an insulin mimetic effect and was an effective glucose-lowering agent in insulinopenic states, acting directly on skeletal muscle. Conversely chamaemeloside appeared to improve glucose tolerance without directly altering glucose transport. Metformin directly increased basal glucose uptake independently of PI 3-kinase, possibly via an increase in the intrinsic activity of glucose transporters. Neither tolbutamide nor thiazolidinediones directly altered insulin sensitivity in L6 skeletal muscle cells: however vanadyl sulphate and thioctic acid increased glucose transport but appeared to exert toxic effects at therapeutic concentrations. Examination of glucose transport in skeletal muscle in this thesis has identified various components of post-receptor insulin signalling pathways which may be targeted to ameliorate insulin resistance. Type 2 Diabetes Mellitus Obesity L6 Skeletal Muscle Cells Glucose Transport Insulin Signalling 2

Candidacidal potential of licorice phenolic extract: emphasis on its mode of action

Medicinal plants bave gained a special attention in the last years, due to its renowned health benefits, such as antimicrobial effects [I]. In fact, several natural matrices bave been increasingly studied, namely for its antifungal activity against opportunistic fungi [2,3]. Candida species, although commensa! microorganisms, have caused severe organic dysfunctions to the host, once current antifungal agents have lost their recognized efficiency [2]. So, numerous studies have been carried out focusing the mechanisms of acquired drug-resistance by Candida species [actions, morphological changes and related kinetic parameters are of major importance. Glycyrrhiza glabra L. (licorice) hydromethanolic extract have evidenced promissory candidacidal effects, and therefore, the involved mechanisms of action need to be clarified. Thus, in the present study these modes of action were assessed, by using flow cytometry.Overall, the licorice extract induced significant and irreversible primary damages on Candida cells, being membrane disruption and consequent unviability one of the main targets. In fact, after membrane destabilization, cells lost their proper homeostasis, their metabolic functions were blocked and, consequently cells lost functionality. The relevance and interest of the achieved results open new insights towards the upcorning use of the present phenolic matrix, being important to evaluate its in viva efficacy. Therefore, further studies are necessary to deepen knowledge on this field, aiming not only to establish therapeutic and prophylactic doses, but also to improve the clinical intervention in Candida infections.

Ecological approaches to cognition and action in sport and exercise : ask not only what you do, but where you do it

In recent decades, concepts and ideas from James J. Gibson’s theory of direct perception in ecological psychology have been applied to the study of how perception and action regulate sport performance. This article examines the influence of different streams of thought in ecological psychology for studying cognition and action in the diverse behavioural contexts of sport and exercise. In discussing the origins of ecological psychology it can be concluded that psychologists such as Lewin, and to some extent Heider, provided the initial impetus for the development of key ideas. We argue that the papers in this special issue clarify that the different schools of thinking in ecological psychology have much to contribute to theoretical and practical developments in sport and exercise psychology. For example, Gibson emphasized and formalized how the individual is coupled with the environment; Brunswik raised the issue of the ontology of probability in human behaviour and the problem of representative design for experimental task constraints; Barker looked carefully into extra-individual behavioural contexts and Bronfenbrenner presented insights pertinent to the relations between behaviour contexts, and macro influences on behaviour. In this overview, we highlight essential issues from the main schools of thought of relevance to the contexts of sport and exercise, and we consider some potential theoretical linkages with dynamical systems theory.

Ticagrelor, a platelet aggregation inhibitor for the potential prevention and treatment of arterial thrombosis and acute coronary syndromes

Ticagrelor is an orally active ADP P2Y12 receptor antagonist in development by AstraZeneca plc for the reduction of recurrent ischemic events in patients with acute coronary syndromes (ACS). Prior to the development of ticagrelor, thienopyridine compounds, such as clopidogrel, were the focus of research into therapies for ACS. Although the thienopyridines are effective platelet aggregation inhibitors, they are prodrugs and, consequently, exert a slow onset of action. In addition, the variability in inter-individual metabolism of thienopyridine prodrugs has been associated with reduced efficacy in some patients. Ticagrelor is not a prodrug and exhibits a more rapid onset of action than the thienopyridine prodrugs. In clinical trials conducted to date, ticagrelor was a potent inhibitor of ADP-induced platelet aggregation and demonstrated effects that were comparable to clopidogrel. In a phase II, short-term trial, the bleeding profile of participants treated with ticagrelor was similar to that obtained with clopidogrel; however, an increased incidence of dyspnea was observed - an effect that has not been reported with the thienopyridines. Considering the occurrence of dyspnea, and the apparent non-superiority of ticagrelor to clopidogrel, it is difficult to justify a clear benefit to the continued development of ticagrelor. Outcomes from an ongoing phase III trial comparing ticagrelor with clopidogrel in 18,000 patients with ACS are likely to impact on the future development of ticagrelor.

Unlocking the potential through Creative Commons

In November 2006, the Australian Research Council Centre of Excellence for Creative Industries and Innovation (CCi), in conjunction with the Queensland University of Technology, hosted the CCau Industry Forum, a research-focused industry engagement event. The event was run by the CCi ccClinic and CC + OCL Research projects, and aimed to evaluate understanding of and attitudes towards copyright, OCL and CC in Australia. The Forum focused on the government, education and the creative industries sectors. Unlocking the Potential Through Creative Commons: An Industry Engagement and Action Agenda evaluates and responds to the outcomes of this Forum and presents a strategy for continued research into Creative Commons in Australia.

The interactive potential of Web 2.0

Following the position of Beer and Burrows (2007) this paper poses a re-conceptualization of Web 2.0 interaction in order to understand the properties of action possibilities in and of Web 2.0. The paper discusses the positioning of Web 2.0 social interaction in light of current descriptions, which point toward the capacities of technology in the production of social affordances within that domain (Bruns 2007; Jenkins 2006; O’Reilly 2005). While this diminishes the agency and reflexivity for users of Web 2.0 it also inadvertently positions tools as the central driver for the interactive potential available (Everitt and Mills 2009; van Dicjk 2009). In doing so it neglects the possibility that participants may be more involved in the production of Web 2.0 than the technology that underwrites it. It is this aspect of Web 2.0 that is questioned in the study with particular interest on how an analytical option may be made available to broaden the scope of investigations into Web 2.0 to include a study of the capacity for an interactive potential in light of how action possibilities are presented to users through communication with others (Bonderup Dohn 2009).